Chronic Cisplatin Treatment Promotes Enhanced Damage Repair and Tumor Progression in a Mouse Model of Lung Cancer

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2010 Apr 17

PMID 20395368

Citations 120

Authors

Trudy G Oliver

Kim L Mercer

Leanne C Sayles

James R Burke

Diana Mendus

Katherine S Lovejoy

Mei-Hsin Cheng

Aravind Subramanian

David Mu

Scott Powers

Denise Crowley

Roderick T Bronson

Charles A Whittaker

Arjun Bhutkar

Stephen J Lippard

Todd Golub

Juergen Thomale

Tyler Jacks

E Alejandro Sweet-Cordero

Affiliations

Soon will be listed here.

Abstract

Chemotherapy resistance is a major obstacle in cancer treatment, yet the mechanisms of response to specific therapies have been largely unexplored in vivo. Employing genetic, genomic, and imaging approaches, we examined the dynamics of response to a mainstay chemotherapeutic, cisplatin, in multiple mouse models of human non-small-cell lung cancer (NSCLC). We show that lung tumors initially respond to cisplatin by sensing DNA damage, undergoing cell cycle arrest, and inducing apoptosis-leading to a significant reduction in tumor burden. Importantly, we demonstrate that this response does not depend on the tumor suppressor p53 or its transcriptional target, p21. Prolonged cisplatin treatment promotes the emergence of resistant tumors with enhanced repair capacity that are cross-resistant to platinum analogs, exhibit advanced histopathology, and possess an increased frequency of genomic alterations. Cisplatin-resistant tumors express elevated levels of multiple DNA damage repair and cell cycle arrest-related genes, including p53-inducible protein with a death domain (Pidd). We demonstrate a novel role for PIDD as a regulator of chemotherapy response in human lung tumor cells.

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